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The renin-angiotensin-aldosterone system (RAAS) plays an important part in the pathogenesis of arterial hypertension and the complications it causes in organs (the heart, the circulatory system, the brain, the kidneys), heart failure and kidney diseases. Materials that block the most upstream point of the RAAS cascade (ACE inhibitors - ACEI, AT1,-receptor (AT1R) blockers, aldosterone receptor blockers) have greatly expanded our options in the treatment and primary and secondary prevention of cardiovascular and renal diseases. ACEI and AT1R blockers interrupt the normal feedback provided by the release of renin into the circulatory system from the kidneys. After they are applied the reactive increase in active circulating renin leads to increased creation of angiotensin I and angiotensin II and the subsequent return of aldosterone secretions to pre-treatment values ("escape" phenomenon). The possible negative effect of these intermediary products of an incomplete blockade of RAAS on organ complications lead to an effort to develop a material that could block the renin-angiotensin cascade at its first stage--i.e. a renin blocker. The first efforts with renin antibodies or peptide analogues of renin prosegments failed to satisify the basic requirements for long-term medication--effectiveness when used orally. In recent years the first non-peptidic, oral renin ihibitor providing sustained effects has been developed, aliskiren fumarate. Aliskiren reduces BP depending on the dose (50-300 mg/day) in monotherapy or in combination with hydrochlorothiazide. Aliskiren lowers plasma renin activity (PRA) and neutralises the activation of the RAAS triggered by hydrochlorothiazide. Ambulatory BP monitoring has shown that taking the medicine once a day has a 24-hour effect and its continued residence in the kidneys suggests renoprotective effects. The compound is in the third stage of clinical tests as a monotherapy or in combination for the treatment of hypertension. It has also been shown to have an influence on the regression of cardiac hypertrophy (Aliskiren in Left-Ventricular Hypertrophy trial - ALLAY), the treatment of heart failure (Aliskiren Observation of Heart Failure Treatment trial - ALOFT) and diabetic (Aliskiren in the Evaluation of Proteinuria in Diabetes trial - AVOID). In April 206, the FDA permitted the use of aliskiren in the USA for the treatment of high BP and it is currently undergoing testing in Europe. The renin inhibitor has minimal undesirable side effects, like AT1-receptor blockers. The slightly lower effectiveness ofaliskiren than AT1-receptor blockers in reducing BP is caused by the fact that it does not block bradykinins. It is recommended as a monotherapy for clinical use or in combination with other antihypertensive medicines for conditions with high levels of PRA including its rise after diuretics, ACEI and AT1-receptor blockers. Aliskiren could therefore be used primarily with young patients, Caucasians, persons with ACEI intolerance, and also in diseases where angiotensin II is involved in the pathogenesis and the secondary prevention of cardiovascular disease. It is also safe for persons with concurrent renal problems, because it is mainly removed by the liver without great interference with other materials. Like ACEI, the renin inhibitor has a vasodilatory effect which could potentially improve the elasticity of arteries. The medicine has the same limitations and contraindications as ACEI and AT1R blockers, such as pregnancy and bilateral renal artery stenosis. A definitive assessment of the benefit of this new class of medicines and its broad application in the treatment of cardiovascular and other diseases will require demonstration of its long-term effect on morbidity and mortality, as well as comparison with other RAAS blockers in long clinical studies, which represent research programmes lasting another 7 to 8 years.
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PMID:[Does the rennin inhibitor aliskiren offer promising novel opportunities in the treatment of cardiovascular diseases?]. 1757 67

The renin-angiotensin-aldosterone-system (RAAS) is an important regulator of blood pressure and fluid-electrolyte homeostasis. RAAS has been implicated in pathogenesis of hypertension, congestive heart failure, and chronic renal failure. Aliskiren is the first non-peptide orally active renin inhibitor approved by FDA. Angiotensin Converting Enzyme (ACE) Inhibitors are associated with frequent side effects such as cough and angio-oedema. Recently, the role of ACE2 and neutral endopeptidase (NEP) in the formation of an important active metabolite/mediator of RAAS, ang 1-7, has initiated attempts towards development of ACE2 inhibitors and combined ACE/NEP inhibitors. Furukawa and colleagues developed a series of low molecular weight nonpeptide imidazole analogues that possess weak but selective, competitive AT1 receptor blocking property. Till date, many compounds have exhibited promising AT1 blocking activity which cause a more complete RAAS blockade than ACE inhibitors. Many have reached the market for alternative treatment of hypertension, heart failure and diabetic nephropathy in ACE inhibitor intolerant patients and still more are waiting in the queue. But, the hallmark of this area of drug research is marked by a progress in understanding molecular interaction of these blockers at the AT1 receptor and unraveling the enigmatic influence of AT2 receptors on growth/anti-growth, differentiation and the regeneration of neuronal tissue. Different modeling strategies are underway to develop tailor made molecules with the best of properties like Dual Action (Angiotensin And Endothelin) Receptor Antagonists (DARA), ACE/NEP inhibitors, triple inhibitors, AT2 agonists, AT1/TxA2 antagonists, balanced AT1/AT2 antagonists, and nonpeptide renin inhibitors. This abstract gives an overview of these various angiotensin receptor antagonists.
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PMID:An update on non-peptide angiotensin receptor antagonists and related RAAS modulators. 1769 38

Initial attempts to inhibit renin in humans have faced numerous difficulties. Molecular modeling and X-ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors such as aliskiren. Aliskiren has a low bioavailability (2.6% to 5%) compensated by its high potency to inhibit renin and a long plasma half-life (24 to 40 h), which makes it suitable for once-daily dosing. The once-daily administration of aliskiren to hypertensive patients lowers blood pressure as strongly as standard doses of established AT1 receptor blockers (losartan, valsartan, and irbesartan), angiotensin-converting enzyme inhibitors (ramipril and lisnopril), hydrochlorothiazide, or long-acting calcium channel blockers (amlodipine). In combination therapy, aliskiren further decreases blood pressure when combined with either hydrochlorothiazide, amlodipine, valsartan, irbesartan, or ramipril. However, the biochemical consequences of renin inhibition differ from those of angiotensin I-converting enzyme inhibition and angiotensin II antagonism, particularly in terms of angiotensin profiles and interactions with the bradykinin-NO-cGMP pathway. Blockade of the renin-angiotensin system with angiotensin I-converting enzyme inhibitors, AT1 receptor blockers, or a combination of these drugs has become one of the most successful therapeutic approaches in medicine. However, it remains unclear how to optimize renin-angiotensin system blockade to maximize cardiovascular and renal benefits. In this context, renin inhibition to render the renin-angiotensin system fully quiescent is a new possibility requiring further study. Preliminary results show that short-term administration of aliskiren has beneficial anti-albuminuric effects in diabetic patients with chronic nephropathy and favorable neurohormonal effects in patients with chronic heart failure.
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PMID:Direct renin inhibition: clinical pharmacology. 2223 43

Hypertension is one of the major health care problems worldwide since it markedly increases the risk for development of heart disease, stroke, generalized vascular disease, and renal failure. The renin-angiotensin system (RAS) with its major end-product angiotensin II (Ang II) plays a fundamental role in blood pressure regulation through direct and indirect mechanisms. Pharmacologically, we can inhibit the RAS using angiotensin-converting enzyme inhibitors and AT1 receptor blocker. Inhibiting renin directly with a clinically useful drug eluded pharmacologists until recently. However, the once-daily, orally effective, small-molecule, direct renin inhibitor aliskiren has recently changed this state of affairs. Aliskiren, with its 40-h half-life and ideal pharmacokinetics, can now address angiotensin production directly at its rate-limiting step. A novel transgenic rat model outfitted with the human renin and angiotensinogen genes allowed the testing of aliskiren in an animal model. Preclinical data demonstrated that aliskiren prolonged survival, decreased cardiac hypertrophy and the inducibility of arrhythmias, proteinuria, and attenuated inflammation. All these features might result in improved target-organ damage. Studies in humans attest to an effective blood pressure-lowering action, a largely side effect-free profile, and the option of several combination therapies. Aliskiren is the first of a novel antihypertensive drug class. The preclinical data is very promising. Nevertheless, for the evaluation of its potency in humans, we have to wait for more clinical data.
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PMID:Aliskiren--mode of action and preclinical data. 1844 51

Hypertension is the most common risk factor for cardiovascular disease, constituting the most common cause of death in industrialized countries. Therefore, the task of blood pressure reduction has significant importance in reducing vascular damage, myocardial infarctions, kidney damage and incidence of cerebrovascular accidents. The renin-angiotensin-aldosterone system (RAAS) plays a central role in control and function of the cardiovascular and renal systems, and is deeply involved in the pathophysiology of diseases of vasculature, heart, kidneys and others. Therefore, blockade of RAAS by angiotensin converting enzyme (ACE) inhibitors and blockers of angiotensin II type AT1 receptors (ARBs) is widely utilized by clinicians. Indeed, it has long been known that ACE inhibitors and ARBs protect different targets of angiotensin II, due to impedance of the negative effects of the hormone and the inhibition of aldosterone production, which contributes both directly and indirectly to the damages, independent of angiotensin II. Despite this, the morbidity and mortality resulting from the progression of cardiovascular diseases in patients treated with ACE inhibitors or ARBs remain high. As such, over the years, much effort has been dedicated to the development of direct inhibitors of renin. The earliest renin inhibitors, developed 30 years ago were not effective due to their protein nature, which prevents their oral administration and limited their clinical use. In the last decade, several non-protein renin inhibitors which could be given orally were developed, of which Aliskiren is the most well known representative. Due to the fact that neutralization of the RAAS by ACE inhibitors and ARBs has been reviewed at length many times, this review will focus on the renewed subject of renin inhibition. The earliest research, both in humans as well as in animal models, show that Aliskiren has therapeutic potential in treatment of patients with hypertension, cardiovascular disease and renal disease. However, the efficacy of Aliskiren in treating systolic and diastolic hypertension in patients was not better than that obtained using ACE inhibitors or ARBs. Even so, there is no need to lower levels of optimism for potential therapy using direct inhibitors of renin. Current research is still in its early stages and there is a need to remember that it took many years to prove the clinical usefulness of ACE inhibitors, which are now central to treatment of cardiovascular and renal diseases, including hypertension.
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PMID:[Oral inhibitors of renin and their potential use as therapeutic agents in treating hypertension]. 1869 32

Aliskiren (Rasilez) is the first oral renin inhibitor. Its present indication is essential hypertension, as monotherapy or in combination with other antihypertensive agents (diuretic, calcium antagonist, ...). It may also be associated with an angiotensin converting enzyme inhibitor (or an AT1 angiotensin receptor antagonist) in order to benefit of a dual blockade of the renin-angiotensin-aldosterone system. The usual daily dose is 150 mg, to be increased up to 300 mg if necessary. New clinical trials are ongoing to validate this novel therapeutic approach in other indications such as congestive heart failure and diabetic nephropathy.
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PMID:[Aliskiren (Rasilez), direct renin inhibitor]. 1905 13

Aliskiren (Rasilez), a direct renin inhibitor, is currently indicated for the treatment of essential hypertension, as monotherapy or in combination, especially with hydrochlorothiazide (Rasilez HCT). It may also be use to obtain a more complete blockade of the renin-angiotensin-aldosterone system (RAAS) when it is associated with an angiotensin converting enzyme inhibitor (ACEI) (or an AT1 angiotensin receptor antagonist) (ARA). There is some room for agents that may be more efficacious in reducing the progression of diabetic nephropathy than ACEI or ARA. In this context, the dual blockade of RAAS most probably offers a better efficacy than the simple blockade, but also exposes to a higher risk. Should ongoing trials confirm the preliminary favourable results, aliskiren might reach a forefront position among the armamentarium now available to optimize the RAAS blockade. The present article will summarize advances concerning the biochemical effects of the specific mode of action of aliskiren, especially the potential interferences related to increased renin/pro-renin levels, as well as results of recent clinical trials, not only in hypertension, but also in the fields of diabetes, renal insufficiency and cardiology. The objectives and design of the landmark study ALTITUDE will also be briefly presented.
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PMID:[Advances concerning aliskiren, direct renin inhibitor and aliskiren-hydrochlorothiazide]. 2006 69

The importance of the renin angiotensin system (RAS) in blood pressure and electrolyte regulation has been well established. High RAS activity results in over-activation of the angiotensin AT1-receptor by its substrate, angiotensin II (AII), leading to increases in BP and direct growth-promoting effects on tissues that result in end-organ damage. The antihypertensive therapies, such as ACE inhibitors and angiotensin AT1-receptor blockers (ARBs) have proved to be successful treatments for hypertension, heart failure, and other related cardiovascular and renal disorders. However, these compounds do not completely inhibit the RAS as a result of AII formation by indirect pathways and compensatory feedback mechanisms, resulting in renin release. Thus renin inhibition has been identified as the preferred pharmacologic approach to blockade of the renin-angiotensin system. The advantages of inhibiting renin in the RAS have been recognized for almost half a century; however major advances in the development of potential clinically effective renin inhibitors have been made only in the past few years with the approval of Aliskiren for clinical use.
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PMID:Renin inhibition--benefit beyond hypertension control. 2032 13

The role of renin-angiotensin-aldosterone system (RAAS) in regulating the volume and composition of extracellular fluid, blood pressure (BP) as well as onset and progression of cardiovascular and renal diseases has been studied for more than 150 years. The compounds that block the vital stages of the RAAS cascade, such as ACE-inhibitors (ACEI), AT1-receptor blockers (ARB) and aldosterone receptor antagonists, importantly extended our treatment options. However, the positive therapeutic effects of these compounds also have certain negative consequences. Administration of ACEIs and ARBs interrupts physiological feedback for renal renin release and leads to reactive elevation of circulating active renin and greater production of angiotensin I and angiotensin II with subsequent return of aldosterone secretion to the pre-treatment levels ('escape' phenomenon). These possible adverse effects of the intermediary products of incomplete RAAS blockade leading to organ complications have facilitated the efforts to develop compounds blocking the initial stages of renin-angiotensin cascade--i.e. direct renin blockers. After several years of unsuccessful attempts, the recent years have seen development of the first non-peptide, orally long-term effective renin inhibitor, aliskiren fumarate. In monotherapy or in combination with other antihypertensives (hydrochlorothiazide, ARB, ACEI), aliskiren reduces BP in a dose-dependent manner (75-600 mg/den). Aliskiren reduces plasma renin activity (PRA) and neutralises hydrochlorothiazide-induced RAAS activation. Once daily administration of the drug leads to longer than 24-hour activity and its prolonged blocking effects on the kidneys are the basis for its renoprotectivity. In addition to the significant antihypertensive effect, clinical studies also showed a range of organoprotective properties in patients with left ventricle hypertrophy (ALLAY study), heart failure (ALOFT study) and diabetic nephropathy (AVOID study). Similar to other AT1-blockers, aliskiren has a minimum of adverse side effects. Aliskiren for hypertension therapy was launched in clinical practice in USA in 2007 (Tekturna and combination formulation TekturnaHCl, respectively) and shortly after that in European Union as Rasilez. In the Czech Republic, aliskiren (Rasilez) was released for clinical use by diabetologists and nephrologists in patients with hypertension and concomitant diabetes, nephropathy and proteinuria in doses of 150-300 mg per day on 1. 8. 2009. It is recommended as monotherapy or in combination with other antihypertensives to treat conditions with elevated PRA, including PRA elevation following diuretic, ACEI or ARB administration. Aliskiren might be used in patients who do not tolerate ACEIs as well as in patients in whom angiotensin II participates in the pathogenesis of their diseases. Reno-protective properties leading to a reduction in proteinuria and delaying renal failure progression were observed in patients with diabetic as well as non-diabetic nephropathy. The drug is the subject to similar precautions and contraindications as ACEIs and ARBs, i.e. pregnancy and bilateral renal artery stenosis. To make meaningful conclusions about the so far positive contribution of this new treatment class and its broad applicability for the therapy of hypertension and other cardiovascular diseases, it will be imperative to assess its long-term effects on morbidity and mortality as well as to compare these agents with other RAAS blockers in long-term clinical studies; this represents a research effort for another 7-8 years.
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PMID:[Direct renin inhibitor aliskiren in the treatment of cardiovascular and renal diseases]. 2032 82

We hypothesized that aliskiren provides renoprotection in diabetic animals that did not receive sufficient renoprotection by AT1-receptor antagonist treatment. Type 2 diabetic KKAy mice were treated with group 1: vehicle or group 2: valsartan (15 mg/kg per day) from 12 to 16 weeks of age. The mice were subsequently divided into 4 groups and treated with the following combinations of drugs for another 6 weeks: 1: group 1 kept receiving vehicle, 2: group 2 continuously received 15 mg/kg per day of valsartan (Val-Val15), 3: group 2 received 50 mg/kg per day of valsartan (Val-Val50), 4: group 2 continuously received 15 mg/kg per day of valsartan with 25 mg/kg per day of aliskiren (Val-Val+Ali). Aliskiren exerted significant anti-albuminuric effects, whereas valsartan failed to ameliorate the albuminuria in the first four weeks. Surprisingly, the increasing dosage of valsartan in the Val-Val50 group showed non-significant tendencies to attenuate the albuminuria compared with vehicle infusion. Val-Val+Ali significantly suppressed the development of albuminuria and podocyte injury. Val-Val50 and Val-Val+Ali showed similar suppression of angiotensin II contents in the kidney of KKAy mice. In conclusion, the anti-albuminuric effect that was observed in the type 2 diabetic mice showing no anti-albuminuric effect by valsartan can be attributed to the add-on aliskiren.
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PMID:Add-on aliskiren elicits stronger renoprotection than high-dose valsartan in type 2 diabetic KKAy mice that do not respond to low-dose valsartan. 2267 48


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